Voluntary participation in clinical studies. Male or female aged ≥ 18 years at the time of signing the ICF. Histologically or cytologically diagnosed with ES-SCLC (according to the Veterans Administration Lung Study Group staging system). No prior systemic therapy for ES-SCLC. At least one measurable lesion as assessed according to RECIST 1.1 within 4 weeks prior to randomization. Major organs are functioning well. Every effort should be made to provide tumor tissues for the determination of PD-L1 expression. An ECOG PS score of 0 or 1. An expected survival ≥ 12 weeks. Subjects with prior denosumab use that can and agree to switch to bisphosphonate therapy for bone metastases starting prior to randomization and throughout treatment. Participant must keep contraception. Histologically or cytologically confirmed mixed SCLC. Known history of severe allergy to any monoclonal antibody. Known hypersensitivity to carboplatin or etoposide. Patients with myocardial infarction within half a year before the first dose of the study drug, poorly controlled arrhythmia. Pregnant or breastfeeding females. Patients with a known history of psychotropic drug abuse or drug addiction. Patients who have other factors that could lead to the early termination of this study based on the investigator's judgment.

1. Patient has signed the informed consent before all study specific activities are conducted. 2. Women or men aged ≥18 years (or the minimum age of consent in accordance with the local law), at the time of informed consent signature. Female patients may be of any menopausal status.
• Postmenopausal status is defined by: 1. Age ≥60 years 2. Age <60 years and amenorrhea for 12 or more months (in the absence of chemotherapy, tamoxifen, toremifene, or ovarian suppression) or a follicle-stimulating hormone (FSH) value >40 mIU/mL and an estradiol value<40 pg/mL (140 pmol/L) or in postmenopausal ranges per local reference ranges 3. Documentation of prior surgical sterilization (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, at least 1 month before first dose of trial therapy).
• Premenopausal and perimenopausal women (who do not fit postmenopausal criteria) and men must be concurrently receiving a luteinizing hormone-releasing hormone (LHRH) agonist initiated at least 4 weeks before the start of trial therapy and are planning to continue LHRH agonist treatment during the study treatment.
• For perimenopausal women to be considered of non-childbearing potential, FSH levels must be >40 mIU/ml. 3. Histopathological or cytological confirmed ER+, HER2-, breast cancer, per local laboratory, as per the American Society of Clinical Oncology (ASCO)/College of American Pathologists(CAP) guidelines (Allison et al, 2020, Wolff et al, 2018). Note: In the context of this trial, ER status will be considered positive if ≥10% of tumor cells demonstrate positive nuclear staining by immunohistochemistry, with or without PGR positivity. . 4. At least 1 not previously irradiated measurable lesion as per RECIST version 1.1 and/or at least 1 lytic or mixed (lytic +sclerotic) bone lesion with identifiable soft tissue components meeting the definition of measurability by RECIST version 1.1 that can be evaluated by CT or MRI; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible. 5. ECOG performance status of 0 or 1. 6. Patient has adequate bone marrow and organ function, as defined by the following laboratory values: 1. Absolute neutrophil count (ANC) ≥1.5 × 10^9/L 2. Platelets ≥100 × 10^9/L 3. Hemoglobin ≥9.0 g/dL 4. Potassium, sodium, calcium (corrected for serum albumin) and magnesium CTCAE grade ≤1 5. Creatinine is ≤ 1.5 x ULN or if creatinine is > 1.5 x ULN, then creatinine clearance must be ≥50 mL/min based on the Cockcroft-Gault formula. Note: C-G formula:
• Creatinine clearance (male) = ([140-age in years] × weight in kg)/ ([serum creatinine in mg/dL] × 72)
• Creatinine clearance (female) = (0.85 × [140-age in years] × weight in kg)/ ([serum creatinine in mg/dL] × 72) 6. Serum albumin ≥3.0 g/dL (≥30 g/L) 7. In absence of liver metastases, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × ULN. If the patient has liver metastases, ALT and AST ≤ 5 × ULN 8. Total serum bilirubin <1.5 × ULN except for patients with Gilbert's syndrome who may be included if the total serum bilirubin is ≤3.0 × ULN or direct bilirubin ≤ 1.5 × ULN. 1. Active or newly diagnosed CNS metastases, including meningeal carcinomatosis. Note: Patients with stable brain or subdural metastases are allowed if the patient has completed local therapy and was on a stable or decreasing dose of corticosteroids at baseline for management of brain metastasis for at least 4 weeks before starting treatment in this study. The dose must be ≤2.0 mg/day of dexamethasone or equivalent. Any signs (e.g., radiologic) or symptoms of brain metastases must be stable for at least 4 weeks before starting study treatment. 2. Patients with advanced, symptomatic visceral spread, that are at risk of life-threatening complications in the short term, including massive uncontrolled effusions (peritoneal, pleural, pericardial), pulmonary lymphangitis, or liver involvement >50%. 3. Prior chemotherapy or elacestrant in the advanced/metastatic setting. 4. Patients with known germline BRCA mutation without prior treatment with a PARP inhibitor before study entry. 5. Prior therapy with elacestrant or other investigational selective estrogen receptor degraders (SERDs), or investigational alike agents such as selective estrogen receptor modulators (SERM), selective estrogen receptor covalent antagonists (SERCANs), complete estrogen receptor antagonists (CERANs), and proteolysis-targeting chimeras (PROTACs), in the metastatic setting. Prior treatment with fulvestrant is not exclusionary as it is an approved medication. 6. Patient has a concurrent malignancy or history of invasive malignancy within 3 years of enrollment, except basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix that has completed curative therapy. Other malignancies with low risk of recurrence may be considered eligible with Sponsor approval. 7. Uncontrolled significant active infections. • Patients with HBV and/or HCV infection must have undetectable viral load during screening. • Patients known to be HIV+ are allowed if they have undetectable viral load at baseline. 8. Documented pneumonitis/ILD prior to Cycle 1 Day 1. 9. Major surgery within 28 days before starting trial therapy. 10. Inability to take oral medications, refractory or chronic nausea, gastrointestinal conditions (including significant gastric or bowel resection), history of malabsorption syndrome, or any other uncontrolled gastrointestinal condition that impact the absorption of the study drug. 11. Known intolerance to elacestrant or any of its excipients. 12. Pregnant and breast-feeding women are excluded from the study. In addition, women of childbearing potential are excluded who: • Within 28 days before starting trial therapy, did not use a highly effective method of contraception. • Do not agree to use a highly effective method of contraception (Appendix F) or abstain from heterosexual intercourse throughout the entire study period and for 120 days after trial therapy discontinuation. 13. Men or women who do not agree to abstain from donating sperm or ova, or to use a highly effective method of contraception, during the course of the treatment period and for 120 days after the last dose of study treatment. 14. Patient is currently receiving or received any of the following medications prior to first dose of trial therapy: • Anti-cancer therapy within 14 days (28 days for anticancer antibody based treatment) or 5 half-lives, whichever is shorter. Please note: Toxicity from prior therapy must be resolved to NCI CTCAE version 5.0 Grade ≤1, except alopecia and peripheral sensory neuropathy (Grade ≤2). • Known strong or moderate inducers or inhibitors of cytochrome P450 (CYP) 3A4 within 14 days or 5 half-lives, whichever is shorter, (refer to http://medicine.iupui.edu/clinpharm/ddis/ or https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interac tions-table-substrates-inhibitors-and-inducers). • Herbal preparations/medications within 7 days. These include, but are not limited to, St. John's wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. • Vaccination, including but not limited to vaccination against COVID-19, during the 7 days prior to randomization. 15. Evidence of ongoing alcohol or drug abuse as assessed by the investigator. 16. Any severe medical or psychiatric condition that, in the Investigator's opinion, would preclude the patient's participation in a clinical study. Additional Eligibility for the Alpelisib Combination (Phase 1b and Arm A) Inclusion: In general, the SmPC of the respective combination drug should be consulted for instructions/restrictions with respect to interactions with concomitant medications. 1. PIK3CA mutation by local laboratory assessment. 2. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor. Exclusion: 1. Prior therapy with alpelisib or any other PI3K inhibitor. 2. Type 1 diabetes or uncontrolled type 2 diabetes (fasting plasma glucose level of >140 mg/dL [7.7 mmol/L], or glycosylated hemoglobin [HbA1c] level of >6.4%). 3. Known intolerance to alpelisib or any of its excipients. 4. Patient is currently receiving or received drugs known to be a BCRP inhibitor within 14 days or 5 half-lives, whichever is shorter, prior to first dose of trial therapy 5. Patient has ongoing osteonecrosis of the jaw from previous or concurrent treatment with bisphosphonates or denosumab Additional Eligibility for the Everolimus Combination (Phase 1b and Arm B) Inclusion: 1. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor. Exclusion: 1. Prior therapy with everolimus. 2. Known intolerance to everolimus or any of its excipients. Additional Eligibility for the Abemaciclib Combination (Arm C) Inclusion: 1. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor. Exclusion: 1. Prior therapy with abemaciclib in the advanced or metastatic setting. Adjuvant therapy with abemaciclib is exclusionary if the patient relapsed within the past 12 months. 2. Known intolerance to abemaciclib or any of its excipients. Additional Eligibility for the Ribociclib Combination (Phase 1b and Arm C) Inclusion: 1. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor. Exclusion: 1. Prior therapy with ribociclib in the metastatic setting. Prior adjuvant therapy with ribociclib is also exclusionary if the patient relapsed within the past 12 months. 2. Known intolerance to ribociclib or any of its excipients. 3. QTcF values ≥450 msec. 4. Patients who already have or who are at significant risk of developing QTc prolongation, including patients with:
• Long QT syndrome
• Uncontrolled or significant cardiac disease including recent (6 months) myocardial infarction, congestive heart failure, unstable angina, and brady-arrhythmias
• Electrolyte abnormalities 5. Patient is currently receiving or received drugs known to prolong QT interval within 14 days or 5 half-lives, whichever is shorter, before the first dose of trial therapy. Additional Eligibility for the Palbociclib Combination (Phase 1b) Inclusion: 1. One or up to two prior hormonal therapies in the advanced or metastatic setting, one of which was in combination with a CDK4/6 inhibitor. Exclusion: 1. Prior therapy with palbociclib in the metastatic setting. 2. Known intolerance to palbociclib or any of its excipients Additional Eligibility for the Palbociclib Combination (Arm D) Inclusion: 1. One or up to two prior hormonal therapies in the advanced or metastatic setting. Exclusion: 1. Prior therapy with a CDK4/6i in the metastatic setting. 2. Known intolerance to palbociclib or any of its excipients. Additional Eligibility for the Abemaciclib Combination (Arm D) Inclusion: 1. One or up to two prior hormonal therapies in the advanced or metastatic setting. Exclusion: 1. Prior therapy with any CDK4/6i in the metastatic setting. 2. Known intolerance to abemaciclib or any of its excipients. Additional Eligibility for Ribociclib Combination (Arm D) Inclusion: 1. One or up to two prior hormonal therapies in the advanced or metastatic setting. Exclusion: 1. Prior therapy with a CDK4/6i in the advanced or metastatic setting. 2. Known intolerance to ribociclib or any of its excipients. 3. QTcF values ≥450 msec. 4. Patients who already have or who are at significant risk of developing QTc prolongation, including patients with:
• Long QT syndrome
• Uncontrolled or significant cardiac disease including recent (6 months) myocardial infarction, congestive heart failure, unstable angina, and brady-arrhythmias
• Electrolyte abnormalities 5. Patient is currently receiving or received drugs known to prolong QT interval within 14 days or 5 half-lives, whichever is shorter, before the first dose of trial therapy.

• Patient must have enrolled onto EAY191 and must have been given a treatment assignment to ComboMATCH to EAY191-N2 based on the presence of an actionable mutation as defined in EAY191
• The patient must be enrolled on the ComboMATCH Master Registration Trial EAY191
• Note: Patients must fulfill all eligibility criteria outlined in the ComboMATCH Registration Trial EAY191 at the time of registration to EAY191-N2. This includes submission of next-generation sequencing (NGS) data from one of the National Cancer Institute (NCI) credentialed designated laboratories for all potential patients prior to treatment trial assignment. Copy number and allele frequency cutoff as per the Registration protocol
• Patients must have disease that can be safely biopsied and agree to a pre-treatment biopsy or, if disease cannot be safely biopsied, have archival tissue available from within 12 months prior to the date of registration on the ComboMATCH registration trial (EAY191)
• Please note the current actionable marker of interest (aMOI)/actionable alteration list for this treatment trial can be found on the Cancer Trial Support Unit (CTSU) ComboMATCH Registration protocol page
• Please note novel/Dynamic aMOI can be submitted for review per the process described in the ComboMATCH Registration protocol
• A COMBOMATCH TREATMENT TRIAL EAY191-N2 ELIGIBILITY CRITERIA:
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
• Age >= 18
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Histologically or cytologically confirmed invasive breast carcinoma
• Confirmed metastatic disease by either imaging or tissue diagnosis
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and one additional lesion that can be biopsied (primary, metastatic both allowed)
• Patients must have inactivating or inferred inactivating NF1 alterations detected in tumor as determined by the ComboMATCH screening assessment
• The tumor must have been determined to be estrogen receptor (ER) and/or progesterone receptor (PgR) positive assessed by current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline recommendations for hormone receptor testing. Patients with >= 1% ER or PgR staining by immunohistochemistry (IHC) are considered positive
• The tumor must have been determined to be HER2-negative by current ASCO/CAP guidelines
• Prior use of CDK4/6 inhibitor(i) is required
• Prior use of fulvestrant regardless of duration is allowed and will determine treatment assignment
• Up to one line of chemotherapy in metastatic setting is allowed
• Absolute neutrophil count >= 1,500/mm^3
• Platelet count >= 100,000/ mm^3
• Hemoglobin level >= 10 g/dL
• Creatinine clearance (CrCL) of ≥ 30 mL/min by the Cockcroft-Gault formula
• Total bilirubin level =< institutional upper limit of normal
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be =< 5.0 x ULN
• For patients who will be assigned to Cohort 2 (fulvestrant-resistant), a left ventricular ejection fraction (LVEF) assessment must be performed within 12 weeks prior to registration. The LVEF must be >= 50% regardless of the cardiac imaging facility's lower limit of normal. (LVEF assessment performed by echocardiogram is preferred; however, MUGA scan may be substituted based on institutional/situational preferences)
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of registration are eligible for this trial
• ELIGIBILITY CRITERIA FOR COHORT 1, TREATMENT REGIMEN 2 PATIENTS WHO MIGRATE TO COHORT 2: Cohort migration: Patients treated with control treatment fulvestrant who experience disease progression may be eligible to migrate to Cohort 2 and receive combination treatment with binimetinib and fulvestrant. Patients who choose to do so must meet laboratory values and performance status requirements below and should begin treatment within 28 days
• PATIENTS WHO MIGRATE TO COHORT 2: Patient's willingness to migrate to Cohort 2 affirmed
• PATIENTS WHO MIGRATE TO COHORT 2: The patient must have an ECOG performance status of 0-2
• PATIENTS WHO MIGRATE TO COHORT 2: Absolute neutrophil count >= 1,500/mm^3
• PATIENTS WHO MIGRATE TO COHORT 2: Platelet count >= 100,000/ mm^3
• PATIENTS WHO MIGRATE TO COHORT 2: Hemoglobin level >= 10 g/dL
• PATIENTS WHO MIGRATE TO COHORT 2: Total bilirubin level =< institutional upper limit of normal (ULN)
• PATIENTS WHO MIGRATE TO COHORT 2: AST and ALT must be =< 5.0 x ULN
• PATIENTS WHO MIGRATE TO COHORT 2: Creatinine clearance (CrCL) of ≥30 mL/min by the Cockcroft-Gault formula
• PATIENTS WHO MIGRATE TO COHORT 2: A LVEF performed within the last 3 months must be >= 50% regardless of the cardiac imaging facility's lower limit of normal (LVEF assessment performed by echocardiogram is preferred; however, MUGA scan may be substituted based on institutional/situational preferences)
• PATIENTS WHO MIGRATE TO COHORT 2: Pregnancy test according to institutional standards must be negative (for patients of childbearing potential only)
• Concurrent anticancer therapy
• Active autoimmune disease requiring systemic treatment within the past 3 months, documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents
• Active brain metastasis. Brain metastases that have been stable for at least 1 month after completion of treatment are not an exclusion criterion
• History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous, chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration
• Patients will be excluded if they currently have the following risk factors for RVO that are documented prior to the enrollment:
• Known uncontrolled glaucoma with intra-ocular pressures >= 21 mmHg
• Known serum cholesterol >= grade 2.
• Known hypertriglyceridemia >= grade 2
• Known hyperglycemia (fasting) >= grade 2
• Patients with baseline QT corrected for heart rate (QTc) > 500 ms, either induced by medication or congenital long QT syndrome will be excluded due to known side effects of binimetinib
• Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory neuropathy) >= grade 2
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
• Other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results
• Pregnancy or lactation at the time of registration or intention to become pregnant during the study (Note: Pregnancy testing according to institutional standards for patients of childbearing potential)
• For binimetinib, highly effective contraception should be used for at least 30 days after the last dose, and patients should not breastfeed for 3 days after the last dose
• For fulvestrant, highly effective contraception should be used for 1 year after the last dose, and patients should not breastfeed for 1 year after the last dose
• Use of any investigational product within 30 days prior to study entry
• INELIGIBILITY CRITERIA FOR COHORT 1, TREATMENT REGIMEN 2 PATIENTS WHO MIGRATE TO COHORT 2
• PATIENTS WHO MIGRATE TO COHORT 2: Not a candidate for binimetinib in the opinion of the treating investigator

Key
• Availability of tumor tissue (archived and fresh tumor biopsy, if medically feasible)
• Select advanced or metastatic solid tumor that is likely to express CLDN18.2 such as gastric/GEJ, pancreatic and esophageal cancer
• ≥ 18 years of age
• ECOG performance status (PS) 0 or 1 at Screening
• Progressed on or after standard therapy, or are intolerable for available standard therapy, or there is no available standard therapy
• Have at least one measurable extra-cranial lesion as defined by RECIST v1.1
• Adequate organ function
• Life expectancy > 12 weeks
• Ability to understand the nature of this study, comply with protocol requirements, and give written informed consent
• Willingness of men and women of reproductive potential to observe conventional and effective birth control for the duration of treatment and for 3 months following study completion Key
• Pregnant or breastfeeding
• Symptomatic or untreated brain metastases
• Have previously received CLDN18.2 antibody drug conjugates (ADCs) or any ADC containing an auristatin payload (prior monoclonal antibody against CLDN18.2 may be eligible)
• Have peripheral neuropathy Grade ≥2
• Have history of non-infectious pneumonitis/interstitial lung disease
• Have diagnosis of another malignancy, or history of systemic treatment for invasive cancer within last 3 years. Note: Patients with Stage I cancer who have received definitive local treatment and are considered unlikely to recur are eligible. Diagnosis of non-melanoma skin cancer, carcinoma in situ of the cervix or breast, or noninvasive tumor does not affect eligibility
• Have active ocular surface disease at baseline (based on screening ophthalmic examination)
• Have serious concurrent illness or clinically relevant active bacterial, fungal or viral infection
• Have previous hypersensitivity to any known components of EO-3021 or history of severe infusion reaction or hypersensitivity (CTCAE Grade 3 or higher) with monoclonal antibody treatment
• Clinically significant cardiac disease, including but not limited to symptomatic congestive heart failure, unstable angina, acute myocardial infarction within 6 months of planned first dose, or unstable cardiac arrhythmia requiring therapy (including torsades de pointes)
• Have history of allogenic hematopoietic stem cell transplantation or solid organ transplantation with ongoing systemic immunosuppressive therapy
• Patients who are not appropriate candidates for participation in this clinical study for any other reason as deemed by the Investigator

• Confirmed diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and active disease clearly documented to initiate therapy.
• Deletion (Del) (17p) status, tumor protein 53 (TP53) mutation status, immunoglobulin heavy chain gene (IGHV) mutation status and Bruton's tyrosine kinase (BTK)-C481 mutation status results required before randomization for Part 2 participants only.
• Relapsed or refractory to at least 1 prior available therapy.
• Have at least 1 marker of disease burden.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 within 7 days before randomization.
• Has a life expectancy of at least 3 months.
• Has the ability to swallow and retain oral medication.
• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV deoxyribonucleic acid (DNA) viral load before randomization.
• Participants with history of hepatitis C virus (HCV) infection are eligible if HCV ribonucleic acid (RNA) viral load is undetectable at screening.
• Participants with human immunodeficiency virus (HIV) who meet ALL eligibility criteria.
• Participants with adequate organ function with specimens collected within 7 days before the start of study intervention.
• If capable of producing sperm, participant agrees to eliminate Nemtabrutinib: 12 days, Venetoclax: 1 month (30 days), Rituximab (rituximab biosimilar): not applicable; abstains from penile-vaginal intercourse as their preferred and usual lifestyle; OR uses prescribed contraception.
• Participant assigned female sex at birth are eligible to participate if not pregnant or breastfeeding and are not a person of childbearing potential (POCBP) OR is a POCBP and uses a contraceptive method that is highly effective, has a negative highly sensitive pregnancy test, and abstains from breastfeeding.
• Has an active hepatitis B virus/ hepatitis C virus (HBV/HCV) infection.
• Has gastrointestinal (GI) dysfunction that may affect drug absorption.
• Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
• Has diagnosis of Richter Transformation or active central nervous system (CNS) involvement by CLL/SLL.
• Has an active infection requiring systemic therapy, such as intravenous (IV) antibiotics, during screening.
• HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease and/or acquired immune deficiency syndrome (AIDS)-defining opportunistic infection in the past 12 months before screening.
• Has QT interval corrected (QTc) prolongation or other significant electrocardiogram (ECG) abnormalities.
• Has a known allergy/sensitivity to nemtabrutinib or contraindication to venetoclax/rituximab (or rituximab biosimilar), or any of the excipients.
• Has history of severe bleeding disorders (eg, hemophilia).
• Has received prior systemic anticancer therapy within 5 half-lives or 4 weeks (if prior therapy was a monoclonal antibody) before randomization.
• Has received prior B-cell lymphoma 2 inhibitor(s) (BCL2i) including venetoclax or Non-covalent Bruton's tyrosine kinase inhibitor (BTKi).
• Is currently being treated with p-glycoprotein (P-gp) substrates with a narrow therapeutic index, cytochrome P450 3A (CYP3A) strong or moderate inducers or CYP3A strong inhibitors.
• Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention.
• Has received an investigational agent or has used an investigational device within 4 weeks before study intervention administration.
• Has a known psychiatric or substance use disorder that would interfere with the participant's ability to cooperate with the requirements of the study.
• Participants who have not adequately recovered from major surgery or have ongoing surgical complications.

1. Adult participants must be 18 years of age or older 2. Advanced or metastatic solid tumors excluding primary central nervous system (CNS) tumors 3. Have documented evidence of genetic alterations conferring homologous recombination deficiency 4. Participant must have progressed on at least one prior line of therapy in the advanced or metastatic setting that is considered an appropriate standard of care, or for which the participant has documented intolerance 1. Known primary CNS malignancy 2. Impairment of GI function or GI disease that may significantly alter the absorption of IDE161 3. Have active, uncontrolled infection 4. Clinically significant cardiac abnormalities 5. Major surgery within 4 weeks prior to enrollment 6. Radiation therapy within 2 weeks prior to enrollment 7. Systemic cytotoxic chemotherapy within 4 weeks prior to enrollment 8. Radioimmunotherapy within 6 weeks of enrollment 9. Treatment with a therapeutic antibody within 4 weeks prior to enrollment 10. Treatment with an anti-cancer small molecule within 5 half-lives (t1/2), or 2 weeks, whichever is shorter

• Willing to provide informed consent.
• Must have a metastatic melanoma diagnosis (stage IV) for which treatment with ipilimumab, nivolumab, and/or pembrolizumab, either alone or in combination with other ICI therapy, is planned.
• Must be planning to participate in Signatera™ (ctDNA level) monitoring with standard of care laboratory testing routinely obtained for treatment with ICI therapy.
• Individuals at least 18 years of age.
• Women of childbearing potential must be willing to use effective contraception as discussed with their oncologist while participating in this study.
• Willing to comply with all study procedures and be available for the duration of the study.
• Not able to receive treatment with ICI therapy
• Use of investigational drugs, biologics, or devices within 30 days prior to enrollment.
• Women who are pregnant, lactating, or planning on becoming pregnant during the study.
• Not suitable for study participation due to other reasons at the discretion of the investigators.

• Alive (per medical record)
• Diagnosed with cancer in the past 3 years
• Received care from a participating oncology clinic in the past year
• Has a current tobacco use status
• Does not have a preferred language other than English (missing language preference will be included).
• Valid address that is not a correctional facility or residential treatment/care facility.
• No flag for patient cognitive impairment, activated health care power of attorney, or other health care agent (e.g., legally authorized representative) in the EHR. The following additional inclusion criteria must be met for inclusion in the CET
• Smoked combustible cigarettes in the past month.
• Able to speak and understand English.
• Willing to set a date to quit smoking in the next 60 days.
• Willing to receive smoking treatment information.
• Willing to complete study activities.
• No current suicidal ideation.
• Suicide attempt in the past year.
• Currently receiving treatment for bipolar disorder, schizophrenia, schizoaffective disorder, or psychotic disorder.
• Incarceration.
• Unable to provide informed consent to treatment (i.e., cannot answer questions about study procedures or risks after hearing about the study).

1. Male or female participants ≥18 years of age 2. Dose Escalation Phase (Part 1): 1. Participants must have a pathologically confirmed diagnosis of an advanced or metastatic solid tumor with a documented RAS, NF1, or RAF mutations. A molecular pathology report documenting mutational status of RAS, NF1, or RAF must be available. 2. Progressed despite standard therapies, and received at least 1 prior line of anticancer therapy.
• Participants with a documented mutation in BRAF V600E or V600K must have received approved treatments known to provide clinical benefit prior to study entry. 3. Participants enrolled in the DCC-3116 and sotorasib cohort (Cohort D) must have a KRAS G12C mutation. 3. Dose Expansion Phase (Part 2): 1. Cohort 1: Patients with Pancreatic Ductal Adenocarcinoma (PDAC).
• Pathologically confirmed PDAC with a documented mutation in KRAS.
• Received only 1 prior line of systemic therapy in the advanced or metastatic setting. 2. Cohort 2: Patients with Non-Small Cell Lung Cancer (NSCLC)
• Pathologically confirmed NSCLC with a documented mutation in KRAS, NRAS, NF1, or BRAF.
• Received at least 2 prior lines but no more than 4 prior lines of systemic therapy in the advanced or metastatic setting. 3. Cohort 3: Patients with Colorectal Cancer (CRC)
• Pathologically confirmed CRC with a documented mutation in KRAS, NRAS, NF1, or BRAF.
• Received at least 2 prior lines of systemic therapy in the advanced or metastatic setting. 4. Cohort 4: Patients with Melanoma
• Pathologically confirmed melanoma with a documented mutation in NRAS.
• Received at least 1 but not more than 2 prior lines of systemic therapy in the advanced or metastatic setting that included T-cell checkpoint inhibitor-based therapy.
• Have not received prior MEK inhibitor therapy. 5. Cohort 5: Patients with KRAS G12C mutant NSCLC
• Pathologically confirmed NSCLC with a documented mutation in KRAS G12C.
• Received at least 1 prior line but no more than 3 prior lines of systemic therapy in the advanced or metastatic setting.
• Have not received prior sotorasib or other KRAS G12C inhibitor therapy. 4. Must provide a fresh tumor biopsy from a primary or metastatic cancer lesion that can be biopsied with acceptable risk as determined by the Investigator, and an archival tumor tissue sample, if available. If a fresh tumor biopsy is not possible, then an archival tumor tissue sample must be provided. 5. Eastern Cooperative Oncology Group (ECOG) score of 0 to 2 (Dose Escalation) or 0 to 1 (Dose Expansion) at Screening 6. Adequate organ function and bone marrow function. 7. If a female of childbearing potential must have a negative pregnancy test prior to enrollment and agree to follow the contraception requirements. 8. Male participants must agree to follow contraception requirements. 9. Must provide signed consent to participate in the study and is willing to comply with study-specific procedures. 1. Must not have received the following within the specified time periods prior to the first dose of study drug: 1. Prior therapies (anticancer or therapies given for other reasons) that are known strong or moderate inhibitors or inducers of CYP3A4 or P-gp including certain herbal medications (eg, St. John's Wort): 14 days or 5× the half-life of the medication (whichever is longer) 2. All other prior anticancer therapies or any therapy that is investigational for the participant's condition with a known safety and PK profile: 14 days or 5× the half-life of the medication (whichever is shorter) 3. Investigational therapies with unknown safety and PK profile: 28 days. If there is enough data on the investigational therapy to assess the risk for drug.-drug interactions and late toxicities of prior therapy as low, the Sponsor's Medical Monitor may approve a shorter washout of 14 days 4. Grapefruit or grapefruit juice: 14 days 2. Have not recovered from all toxicities from prior therapy according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). 3. Presence or history of central nervous system (CNS) metastases or leptomeningeal disease, with some exceptions 4. New York Heart Association Class III or IV heart disease, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension, congestive heart failure, or myocardial infarction within 6 months prior to the first dose of study drug. 5. Prolongation of the QT interval corrected by Fridericia's formula (QTcF) based on repeated demonstration of QTcF >450 ms in males or >470 ms in females at screening, or history of long QT syndrome. 6. Left ventricular ejection fraction (LVEF) <50% at Screening 7. Systemic arterial thrombotic or embolic events 8. Systemic venous thrombotic events 9. Malabsorption syndrome 10. Bone disease that requires ongoing treatment or has required treatment. 11. Major surgery within 4 weeks of the first dose of study drug. All surgical wounds must be healed and free of infection or dehiscence before the first dose of the study drug. 12. Any other clinically significant comorbidities. 13. For participants receiving DCC-3116 and trametinib combination or DCC-3116 and binimetinib combination: previous treatment with trametinib or binimetinib that resulted in treatment discontinuation due to intolerability as a result of an adverse event (AE) that was considered related to trametinib or binimetinib. 14. For participants receiving DCC-3116 and sotorasib combination in Dose Escalation Part 1: previous treatment with sotorasib that resulted in treatment discontinuation due to intolerability as a result of an adverse event (AE) that was considered related to sotorasib. 15. For participants receiving DCC-3116 and sotorasib combination: Use of proton pump inhibitors (PPIs) and H2 receptor antagonists that cannot be discontinued 3 days prior to the start of study drug administration. 16. Known allergy or hypersensitivity to any component of the investigational drug products. 17. Known human immunodeficiency virus unless the following requirements are met: 1. CD4 count >350/µL 2. No AIDS-defining opportunistic infection in the last 12 months 3. Stable anti-retroviral regimen with medications that are not prohibited by the protocol for at least 4 weeks with HIV viral load less than 400 copies/mL prior to enrollment. 18. Known active hepatitis B, active hepatitis C infection or if the participant is taking medications that are prohibited per protocol. 19. If female, the participant is pregnant or lactating. 20. Ongoing participation in an interventional study. 21. For participants receiving DCC-3116 and binimetinib combination: Known Gilbert's syndrome

Key
• Patients must have a documented NPM1 mutation or KMT2A rearrangement and have either newly diagnosed or relapsed/refractory AML
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• Adequate liver, renal, and cardiac function according to protocol defined criteria
• A female of childbearing potential must agree to use adequate contraception from the time of screening through 180 days following the last dose of study intervention. A male of childbearing potential must agree to use abstinence or adequate contraception from the time of screening through 90 days following the last dose of study intervention Key
• Diagnosis of either acute promyelocytic leukemia or blast chronic myelomonocytic leukemia
• Known history of BCR-ABL alteration
• Advanced malignant hepatic tumor [for patients receiving ven/aza combination]
• Administration of live attenuated vaccines within 14 days prior to, during, or after treatment until B-cell recovery
• Active central nervous system (CNS) involvement by AML.
• Clinical signs/symptoms of leukostasis or WBC > 25,000 / microliter. Hydroxyurea and/or leukapheresis are permitted to meet this criterion
• Not recovered to Grade ≤1 (NCI-CTCAE v5.0) from all nonhematological toxicities except for alopecia
• Known clinically active human immunodeficiency virus, active hepatitis B or active hepatitis C infection
• For newly diagnosed cohorts: received prior chemotherapy for leukemia, except hydroxyurea and/or leukapheresis to control leukocytosis, prior treatment with all-transretinoic acid for initially suspected acute promyelocytic leukemia, or non-HMA therapy for prior myelodysplastic syndrome
• For relapsed/refractory cohorts: received chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy that is considered to be investigational < 14 days prior to the first dose of ziftomenib or within 5 drug half-lives prior to the first dose of study drug
• Uncontrolled intercurrent illness including, but not limited to, cardiac illness as defined in the protocol
• Mean corrected QT interval corrected for heart rate by Fredericia's formula (QTcF) >480 ms on triplicate ECGs
• Uncontrolled infection
• Women who are pregnant or lactating
• An active malignancy and currently receiving chemotherapy for that malignancy or disease that is uncontrolled/progressing

• A patient cannot be considered eligible for this study unless ALL of the following conditions are met.
• The patient or a legally authorized representative must provide study-specific informed consent prior to pre-entry and, for patients treated in the U.S., authorization permitting release of personal health information.
• Female patients must be greater than or equal to 18 years of age.
• Patients must be premenopausal (evidence of functioning ovaries) at the time of pre-entry. For study purposes, premenopausal is defined as:
• Age 50 years or under with spontaneous menses within 12 months; or
• Age greater than 50-60 years with spontaneous menses within 12 months plus follicle-stimulating hormone (FSH) and estradiol levels in the premenopausal range; or
• Patients with amenorrhea due to IUD or prior uterine ablation must have FSH and estradiol levels in the premenopausal range; or
• Patients with prior hysterectomy must have FSH and estradiol levels in the premenopausal range.
• The patient must have an ECOG performance status of less than or equal to 2 (or Karnofsky greater than or equal to 60%).
• Patients may have ipsilateral or contralateral synchronous breast cancer if the highest stage tumor meets entry criteria, and the other sites of disease would not require chemotherapy or HER2-directed therapy.
• Patients may have multicentric or multifocal breast cancer if the highest stage tumor meets entry criteria, and the other sites of disease would not require chemotherapy or HER2-directed therapy.
• Patient may have undergone a total mastectomy, skin-sparing mastectomy, nipple-sparing mastectomy, or a lumpectomy.
• For patients who undergo a lumpectomy, the margins of the resected specimen or re-excision must be histologically free of invasive tumor and DCIS (ductal carcinoma in situ) with no ink on tumor as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional excisions may be performed to obtain clear margins. Positive posterior margin is allowed if surgeon deems no further resection possible. (Patients with margins positive for LCIS (lobular carcinoma in situ) are eligible without additional resection.)
• For patients who undergo mastectomy, the margins must be free of residual gross tumor. (Patients with microscopic positive margins are eligible if post-mastectomy RT (radiation therapy) of the chest wall will be administered.)
• Patient must have undergone axillary staging with sentinel node biopsy (SNB), targeted axillary dissection (TAD), or axillary lymph node dissection (ALND).
• The following staging criteria must be met postoperatively according to AJCC 8th edition criteria:
• By pathologic evaluation, primary tumor must be pT1-3. (If N0, must be T1c or higher.)
• By pathologic evaluation, ipsilateral nodes must be pN0 or pN1 (pN1mi, pN1a, pN1b, pN1c).
• Patients with positive isolated tumor cells (ITCs) in axillary nodes will be considered N0 for eligibility purposes.
• Patients with micrometastatic nodal involvement (0.2-2 mm) will be considered N1.
• Oncotype DX RS (recurrence score) requirements*:
• If node-negative:
• Oncotype DX RS must be RS 21-25, or
• Oncotype DX RS must be 16-20 and disease must be high clinical risk, defined as: low histologic grade with primary tumor size greater than 3 cm, intermediate histologic grade with primary tumor size greater than 2 cm, or high histologic grade with primary tumor size greater than 1 cm.
• If 1-3 nodes involved:
• Oncotype DX RS must be less than 26. * Patients with a "Low Risk" or "MP1" MammaPrint (a genomic test that analyzes the activity of certain genes in early-stage breast cancer) result must have eligibility assessed with an Oncotype DX RS at pre-entry (see Section 3.1). Blocks or unstained slides must be sent to the Genomic Health centralized laboratory for testing at no cost to these patients. If MammaPrint High Risk or MP2, these patients are not eligible.
• The tumor must be ER and/or PgR-positive (progesterone receptor) by current ASCO/CAP guidelines based on local testing results. Patients with greater than or equal to 1% ER and/or PgR staining by IHC will be classified as positive.
• The tumor must be HER2-negative by current ASCO/CAP (American Society of Clinical Oncology/College of American Pathologists) guidelines based on local testing results.
• The interval between the last surgery for breast cancer (including re-excision of margins) and pre-entry must be no more than 16 weeks.
• Short course of endocrine therapy of less than 6 weeks duration before pre-entry is acceptable either as neoadjuvant or adjuvant therapy. An Oncotype DX RS must be performed on core biopsy specimen obtained prior to initiation of neoadjuvant endocrine therapy if received.
• Patients with a prior or concurrent non-breast malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. This would include prior cancers treated with curative intent.
• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• Radiation therapy should be used according to standard guidelines; the intended radiation therapy should be declared prior to pre-entry.
• • Definitive clinical or radiologic evidence of metastatic disease.
• pT4 (pathological state) tumors, including inflammatory breast cancer.
• History of ipsilateral or contralateral invasive breast cancer. (Patients with synchronous and/or previous DCIS or LCIS are eligible.)
• If prior ipsilateral DCIS was treated with lumpectomy and XRT (ionizing radiation therapy), a mastectomy must have been performed for the current cancer.
• Life expectancy of less than 10 years due to co-morbid conditions in the opinion of the investigator. Known results from most recent lab studies obtained as part of routine care prior to study entry showing ANY of the following values:
• ANC (absolute neutrophil count) less than 1200/mm3;
• Platelet count less than 100,000/mm3;
• Hemoglobin less than 10 g/dL;
• Total bilirubin greater than ULN (upper limit of normal) for the lab or greater than 1.5 x ULN for patients who have a bilirubin elevation due to Gilbert's disease or similar syndrome involving slow conjugation of bilirubin;
• AST(aspartate aminotransferase)(SGOT)/ALT (alanine transminase)(SGPT): greater than 3 × institutional ULN;
• Renal function of GFR (glomular filtration rate) less than 30 mL/min/1.73m2.
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
• Non-epithelial breast malignancies such as sarcoma or lymphoma.
• Any treatment with radiation therapy, chemotherapy, or biotherapy administered for the currently diagnosed breast cancer prior to pre-entry. (Patients with prior ET of more than 6 weeks duration for treatment of this cancer are not eligible.) Prior tamoxifen given for breast cancer prevention is allowed. Prior AI or GnRH for fertility preservation is allowed.
• Hormonally based contraceptive measures must be discontinued prior to pre-entry (including progestin/progesterone IUDs).
• Patients with evidence of chronic hepatitis B virus (HBV) infection are ineligible unless the HBV viral load is undetectable on suppressive therapy. Patients with a history of hepatitis C virus (HCV) infection are ineligible unless they have been treated and cured or have an undetectable HCV viral load if still on active therapy.
• Pregnancy or lactation at the time of pre-entry. (Note: Pregnancy testing according to institutional standards for women of childbearing potential must be performed within 2 weeks prior to pre-entry.)
• Other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements or interfere with interpretation of study results.

• Pathologically (histologically or cytologically) proven diagnosis of stage II or III (American Joint Committee on Cancer [AJCC] eighth edition) non-small cell lung cancer (NSCLC) with known PD-L1 status prior to registration
• Patients must have an identified primary tumor and at least one nodal metastasis (peribronchial/hilar/intrapulmonary, mediastinal/subcarinal, supraclavicular/scalene)
• Up to 4 cycles of systemic therapy received prior to registration for the current study cancer is allowable; any prior chemotherapy for a different cancer is also permissible
• The patient must be deemed clinically appropriate for curative intent definitive combined modality therapy, based on the following staging assessments:
• History/physical examination prior to registration;
• Magnetic resonance imaging (MRI) scan of the brain (preferred) or CT scan of the brain (if available, contrast is preferred for all neuroimaging) prior to registration;
• CT chest with IV contrast (if contrast is available and unless contraindicated, such as for abnormal kidney function) prior to registration. PET/CT may be used if the CT portion is of identical diagnostic quality as achieved in a stand-alone CT
• No evidence of distant metastases based on FDG PET/CT scan obtain within 60 days of registration
• Primary tumor =< 7 cm
• Age >= 18
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Hematologic function (e.g. platelets, leukocytes, hemoglobin) amenable, at the discretion of the treating physician, to allow for treatment with chemotherapy and concurrent radiation therapy
• Creatinine clearance >= 25 mL/min by the Cockcroft-Gault (C-G) equation
• Subjects with non-malignant pleural effusion are eligible provided the effusion is not known or demonstrated to be an exudative effusion
• If a pleural effusion is present, the following criteria must be met to exclude malignant involvement:
• When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative;
• Effusions that are minimal (i.e., not visible on chest x-ray) that are too small to safely tap are eligible
• Medical history consistent with the patient being amenable, at the discretion of the treating physician, to allow for treating with consolidation immunotherapy. Patients with known EGFR/ALK mutation at the time of registration are eligible, and these patients can be treated with consolidation durvalumab or chemotherapy at the discretion of the treating physician
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen
• Negative pregnancy test =< 14 days prior to registration for participants of childbearing potential
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields that is determined by the treating physician to impede the treatment of the study malignancy
• Patients without identifiable primary tumor and at least 1 pathologically enlarged lymph node are not eligible (T3-4N0 or T0N1-3 patients are not eligible). At least 1 radiographically-involved lymph node is required, but pathologic confirmation of involvement is not mandated
• Centrally located primary tumor < 2 cm from involved nodal disease which would result in significant overlap of the primary SBRT and nodal radiation fields. Centrally located is defined as within or touching the zone of the proximal bronchial tree, which is a volume 2 cm in all directions around the proximal bronchial tree (carina, right and left main bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchus right and left lower lobe bronchi)
• Participants who are pregnant or unwilling to discontinue nursing
• Participants of childbearing potential (participants who may become pregnant or who may impregnate a partner) unwilling to use highly effective contraceptives during therapy and for the Food and Drug Administration (FDA)-labeled contraception timeframe required after the final dose of the selected chemotherapy regimen, because the treatment in this study may be significantly teratogenic

1. Patient must have advanced (FIGO 2014 Stage III or IV), persistent, or recurrent endometrial carcinoma, which is not likely to be curable by surgery or radiotherapy. Histologic confirmation of recurrent disease is required. For cases of persistent disease, histologic confirmation of the primary disease with radiologic evidence of progression is required. 2. Patients must have endometrioid histology (all grades allowed) based on hysterectomy or biopsy specimen and have positive expression of ER and oncogenic PIK3CA mutation per criteria below. a. PIK3CA mutations considered oncogenic include R88Q, N345K, C420R, E542K, E545X, Q546X, M1043I, H1047X, or G1049R. The list of oncogenic mutations acceptable for enrollment may be expanded as further information becomes available. i. Oncogenic PIK3CA mutations identified on tests performed by the labs listed on https://ecog-acrin.org/nci-match-eay131-designated-labs will be considered confirmed for the purposes of this study ii. Oncogenic PIK3CA mutations identified by other tests will need to be confirmed by the study prior to enrollment b. Estrogen receptor (ER) status will be considered positive if ≥1% of tumor cells demonstrate positive nuclear staining by immunohistochemistry. Pathology report documenting ER status must be provided at enrollment. Sites are required to report results of previous MMR and/or MSI status testing in Medidata Rave if available. 3. All patients must have measurable disease. Measurable disease is defined by RECIST version 1.1. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded). Each lesion must be greater than or equal to 10mm when measured by CT, MRI or caliper measurement by clinical exam; or greater than or equal to 20mm when measured by chest x-ray. Lymph nodes must be greater than or equal to 15mm in short axis when measured by CT or MRI. Patients must have at least one "target lesion" to be used to assess response on this protocol as defined by RECIST 1.1. Tumors within a previously irradiated field will be designated as "non-target" lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy. 4. Prior chemotherapy in the adjuvant setting for Stage I, II, or III is permitted. Prior chemoradiotherapy for a pelvic recurrence is permitted. Note: No prior chemotherapy in the setting of Stage IV disease is permitted unless the patient was without evidence of disease at the completion of chemotherapy and had a least six months of progression-free survival since the completion of chemotherapy. Regardless of circumstances, no more than one prior chemotherapy regimen (including chemo-radiotherapy) is permitted. Patients who received prior chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for residual alopecia or Grade 2 peripheral neuropathy prior to enrollment. A washout period of at least 21 days is required between last chemotherapy dose and initiation of therapy. Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and initiation of therapy. 5. Patient must be able to swallow oral medications. 6. Patient must have an ECOG performance status of 0 to 1. 7. Patients must have adequate glucose control as defined by the following (both criteria must be met):
• Fasting blood glucose (FBG) ≤140/dL (7.7mmol/L) AND
• Hemoglobin A1c (HbA1c) ≤6.4% 8. Patients must have adequate organ and marrow function as defined below NOTE: Institutional/laboratory upper limit of normal = ULN Institutional/laboratory lower limit of normal = LLN Bone marrow function:
• Absolute neutrophil count (ANC) greater than or equal to 1500/mcl
• Platelets greater than or equal to 100,000 cells/mcl
• Hemoglobin greater than or equal to 8 g/dL (Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after erythrocyte transfusion). Renal function: • Creatinine Clearance ≥ 35 mL/min using Cockcroft-Gault formula Pancreatic function:
• Fasting Serum amylase ≤ 2 × ULN
• Fasting Serum lipase ≤ ULN Hepatic function:
• Bilirubin less than or equal to 1.5 x ULN (Patients with Gilbert's syndrome with a total bilirubin ≤2 times ULN and direct bilirubin within normal limits are permitted).
• ALT (alanine aminotransferase) and AST (aspartate aminotransferase) less than or equal to 3 x ULN
• Alkaline phosphatase less than or equal to 2.5 x ULN
• Albumin greater than or equal to 2.8 g/dL 9. Patients must have signed an approved informed consent and authorization permitting release of personal health information. 10. Patients must be at least 18 years of age. 11. Patients of childbearing potential must have a negative serum pregnancy test prior to the study entry and be practicing a highly effective form of contraception during the study treatment and for 8 weeks after stopping the treatment. Highly effective contraception methods include combination of any of the following (oral, injected, or implanted hormonal contraceptives are prohibited:
• Placement of an intrauterine device (IUD) or intrauterine system (IUS);
• Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository;
• Total abstinence or;
• Male/female sterilization. Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to randomization. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential. 1. Patients who have previously received any PIK3CA, PI3K, mTOR, or AKT inhibitor. 2. Patients with clear cell, serous, carcinosarcoma, mixed histology endometrial cancers, or uterine sarcomas. 3. Known intolerance or hypersensitivity to alpelisib or fulvestrant, or any of their excipients. 4. Patients who have previously received hormonal therapy for endometrial cancer. 5. Participant has had major surgery within 14 days prior to study treatment start and/or has not recovered from major side effects. 6. Participant with an established diagnosis of diabetes mellitus type I or uncontrolled type II (based on fasting blood glucose [FBG] and HemoglobinA1c [HbA1c], see INCLUSION CRITERION 7) 7. Patients with concomitant invasive malignancy or a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the past five years. Patients are also excluded if their previous cancer treatment contraindicates this protocol. 8. Patients with active bacterial infection (requiring intravenous [IV] antibiotics at time of initiating study treatment, fungal infection, or detectable viral infection (such as known human immunodeficiency virus (HIV) positivity or with known active hepatitis B or C [for example, hepatitis B surface antigen positive]). Screening is not required for enrollment. 9. Patients with a serious pre-existing medical condition(s) that would preclude participation in this study (for example: interstitial lung disease or pneumonitis, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment (i.e. estimated creatinine clearance <30ml/min), history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or pre-existing chronic condition resulting in baseline grade 2 or higher diarrhea). 10. Patients with a known history of cardiac disease. This includes:
• Uncontrolled hypertension, defined as systolic greater than 150mm Hg or diastolic greater than 90mm Hg despite antihypertensive medications
• Myocardial infarction, unstable angina, symptomatic pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to registration.
• New York Heart Association (NYHA) Class II or greater congestive heart failure.
• History of clinically significant cardiac arrhythmias (i.e. ventricular tachycardia or ventricular fibrillation, complete left bundle branch block, high grade AV block (e.g. bifascicular block, Mobitz type II and third degree AV block without pacemaker in place) or serious cardiac arrhythmia requiring medication. This does not include asymptomatic atrial fibrillation with controlled ventricular rate.
• Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or Fridericia QT correction formula (QTcF) > 470 msec at screening.
• Cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) within 6 months prior to the first date of study therapy.
• Syncope of cardiovascular etiology,
• Sudden cardiac arrest. 11. Participant is currently receiving any of the following medications and cannot be discontinued 7 days prior to the start of the treatment:
• Strong CYP3A4 inducers
• Inhibitors of BCRP. 12. Patients who are pregnant or breast-feeding. 13. Patients with known central nervous system metastases which was not previously treated and not fulfilling the following 3 criteria to be eligible for the study:
• Completed prior therapy (including radiation and/or surgery) for CNS metastases ≥ 28 days prior to the start of study entry and
• CNS tumor is clinically stable at the time of screening and
• Participant is not receiving steroids and/or enzyme inducing anti-epileptic medications for brain metastases. 14. Patients with an impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the study drugs (i.e. ulcerative disease; uncontrolled nausea, vomiting and/or diarrhea; malabsorption syndrome; clinical signs and symptoms of gastrointestinal obstruction; and/or patients who require parenteral hydration and/or nutrition). 15. Patients who plan to receive live attenuated vaccines within 1 week of start of alpelisib and during the study. Patients should also avoid close contact with others who have received live attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG< yellow fever, varicella, and TY21a typhoid vaccines. 16. Patients with active bleeding or pathologic conditions that carry high risk of bleeding such as known bleeding disorder or coagulopathy. 17. Patients who are currently part of or have participated in any clinical investigation with an investigational drug within 30 days prior to dosing, or within 5 half-lives of the investigational product, whichever is longer. 18. Patient is not able to understand and to comply with study instructions and requirements, including oral administration of study treatment.

1. Subject (or legally authorized representative, where applicable) is willing and able to provide signed informed consent and can follow protocol requirements 2. Subject is ≥18 years of age at time of informed consent 3. Eastern Cooperative Oncology Group performance status of 0 or 1 4. Subject has documented evidence of a BRAF V600 mutation obtained from tumor tissue or liquid biopsy: (other protocol conditions may apply) 5. Subject must have received ≥1 prior line of SoC therapy for their unresectable locally advanced or metastatic disease with disease progression on or after last prior treatment. Prior regimens for these subjects vary by indication and investigational arm, but must have included the following: 1. Melanoma or NSCLC (Phase 1 and Phase 2 Arms A1 and B1): Prior receipt of a BRAF inhibitor and an immune checkpoint inhibitor (any sequence or combination). Prior (neo)adjuvant immunotherapy may be acceptable. 2. CRC: Receipt of a systemic chemotherapy-based regimen per SoC for unresectable locally advanced or metastatic disease, and previous treatment with BRAF inhibitor in combination with an EGFR monoclonal antibody. Subjects with documented MSI-H or dMMR CRC must have received prior immunotherapy. Subjects with MSS disease must have received at least 2 prior treatments. Subjects who received neo(adjuvant) chemotherapy regimens may be eligible. 3. ATC: Subjects must have received SoC therapy options including BRAF inhibitor if available and of benefit to the subject 4. Other BRAF V600 mutant solid tumors (non-CNS): Subjects must have received SoC therapy options per their Investigator's best judgment, including BRAF inhibitor if available and of benefit to the subject 6. Subject has measurable disease per RECIST v1.1 7. Adequate bone marrow, liver, renal, and cardiac function 8. A female subject may be eligible if not pregnant, planning a pregnancy, not breast feeding, a women of non-child bearing potential or a WOCBP willing to comply with protocol conditions relating to the use contraception, ova or blood donation and pregnancy testing prior to the first dose 9. A male subject must agree to comply with protocol conditions relating to the use of contraception, sperm and blood donation 10. Subject can safely swallow a tablet or pill Other protocol defined exclusion criteria may apply 1. Subject has had major surgery within 21 days prior to the planned first dose. Minor surgery is permitted within 21 days prior to enrollment 2. Subject with CNS involvement (primary tumor or metastatic disease), except if clinically stable, have no evidence of new or enlarging brain metastases and are on stable or tapering doses of steroids for at least 7 days prior to first dose. Subjects with untreated brain metastases may be eligible to enter without prior radiation therapy. 3. Subject with known malignancy other than trial indication that is progressing or has required treatment within the past 3 years, except for conditions that have undergone potentially curative therapy 4. Subject with history of thromboembolic or cerebrovascular events ≤6 months as defined in the protocol 5. Subject with impaired cardiac function or clinically significant cardiac disease, as defined in the protocol 6. Subject with history of uncontrolled diabetes mellitus (only for subjects who will receive CFT1946 + trametinib) 7. Subject with history or current evidence of retinal vein occlusion (RVO), chorioretinopathy, or current risk factors for RVO (only for subjects who will receive CFT1946 + trametinib) 8. Subject has received live, attenuated vaccine within 28 days prior to first dose administration 9. Subject has history of pneumonitis or interstitial lung disease 10. Subject has history of uveitis 11. Subject has known human immunodeficiency virus (HIV) infection (with exceptions) 12. Subject has history of or known HBV or active HCV infection 13. Subject has concurrent administration of strong CYP3A4/5 inhibitors and inducers, including any herbal medications/supplements 14. Subject has presence of Grade ≥2 toxicity due to prior cancer therapy, excepting alopecia and hypothyroidism requiring thyroid replacement therapy 15. Subject has initiation or receipt of the following ≤7 days prior to first dose administration: Hematopoietic colony-stimulating growth factors, transfusion of packed red blood cells (pRBC), and transfusion of platelets 16. Subject is pregnant, breastfeeding, or expecting to conceive or father children any time during the study Other protocol defined exclusion criteria may apply

• PHASE 1: Patients must have a histologically confirmed metastatic or locally advanced unresectable solid tumor that has progressed on or after available standard of care therapy or for which no acceptable standard of care therapy exists, or in which the patient declines standard of care therapy (each patient that declines standard of care therapy will be documented in the case report form)
• PHASE 2: Patients must have a histologically confirmed metastatic or locally advanced unresectable cholangiocarcinoma/gallbladder carcinoma that has progressed on at least 1 prior standard of care therapy or for which no acceptable standard of care therapy exists, or in which the patient declines standard of care therapy (each patient that declines standard of care therapy will be documented in the case report form)
• Age >= 18 years
• Because no dosing or adverse event data are currently available on the use of M3814 in combination with avelumab in patients < 18 years of age
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Patients with at least 1 index lesion to irradiate for whom palliative radiation treatment is indicated (including but not limited to pain and/or symptom control, prevention of disease -related complications, and preservation of organ function). Lung and liver lesions are preferred, though alternate lesions may be considered after discussion with trial principal investigator (PI). Up to 2 lesions may be considered for irradiation provided at least 1 lesion will receive the study treatment of total of 60 Gy and all prescribed irradiation will be completed within the radiation window
• Patients with at least 1 Response Evaluation Criteria in Solid Tumors (RECIST) measurable lesion (to be unirradiated) (defined as those accurately measured in at least one dimension, with the longest diameter to be recorded for non-nodal lesions and the shortest diameter for nodal lesions). Measurable is defined as at least 10 mm in longest diameter for solid tumors, at least 15 mm in shortest diameter for lymph nodes
• Patients must be willing to undergo fresh biopsies at baseline (as opposed to using archival tissue), in the event their baseline tissue was obtained > 12 months prior to study consent and/or they are randomized to the gamma H2AX pNBS1 multiplex IFA assay
• Absolute neutrophil count (ANC) >= 1,500/mcL
• Platelet count >= 100,000/mcL
• Hemoglobin >= 9.0 g/dL
• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR calculated serum creatinine clearance (glomerular filtration rate [GFR] can be used in place of creatinine or creatinine clearance) >= 60 mL/min for participants with creatinine levels > 1.5 x institutional ULN
• Calculate serum creatinine clearance using the standard Cockcroft-Gault formula
• Serum total bilirubin =< 1.5 x ULN or direct bilirubin =< ULN for participants with total bilirubin > 1.5 x ULN
• Patients with known Gilbert disease with serum bilirubin level =< 3 x ULN are eligible
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN or =< 5.0 x ULN for patients with hepatobiliary tumors/liver metastases
• Albumin >= 2.8 g/L
• International normalized ratio (INR) or prothrombin time (PT) or activated partial thromboplastin time (aPTT) =< 1.5 x ULN
• This applies only to patients not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose
• Participants must have the ability to swallow and retain oral medication and not have any clinically significant gastrointestinal abnormalities that might alter absorption
• Female patients of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The effects of M3814 and avelumab on the developing human fetus are unknown and there is the potential for teratogenic or abortifacient effects. For this reason, women and men of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study treatment, and for 6 months after completion of M3814 and avelumab administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M3814 and avelumab, breastfeeding should be discontinued if the mother is treated with M3814 and avelumab
• Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a close caregiver or legally authorized representative (LAR) and/or family member available will also be eligible
• PHASE I: Patients who have received prior anti-CTLA-4, anti-PD-1, anti-PD-L1 or other immune checkpoint inhibitor therapeutic antibodies or pathway-targeting agents
• PHASE II: Patients who have received prior anti-CTLA-4, anti-PD-1, anti-PD-L1 or other immune checkpoint inhibitor therapeutic antibodies or pathway-targeting agents with the following exceptions:
• Patients who have only received previous durvalumab (anti-PD-L1) in combination with gemcitabine +/- cisplatin as part of first line therapy (TOPAZ-1 regimen) are eligible
• Patients who have only received previous pembrolizumab (anti-PD-1) in combination with gemcitabine +/- cisplatin as part of first line therapy (KEYNOTE-966 regimen) are eligible
• Patients who have had chemotherapy, definitive radiation, biological cancer therapy, or investigational agent/device within 21 days of first planned dose of study therapy (within 14 days for palliative radiation). Previously irradiated lesions may be re-irradiated provided there is disease progression in the irradiated lesion and the prescribed radiation dosage can safely be re- administered
• Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Common Terminology Criteria for Adverse Events [CTCAE] grade 1) with the exception of alopecia
• Patients with untreated/uncontrolled central nervous system (CNS)/leptomeningeal disease. Patients with asymptomatic, treated CNS disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy and the following criteria are met:
• Radiographic demonstration of clinical stability upon the completion of CNS-directed therapy and no evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study done >= 4 weeks from completion of radiotherapy and >= 2 weeks from discontinuation of corticosteroids
• No stereotactic radiation or whole-brain radiation within 28 days prior to randomization
• Patients with active autoimmune disease requiring systemic corticosteroids greater than the equivalent of prednisone 10 mg daily including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, colitis, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjogren's syndrome, Bell's palsy, Guillain-Barre syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis, with the following exceptions:
• Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible
• Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are eligible
• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only who require only low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%) are eligible
• Patients receiving treatment with systemic immunosuppressive medications (including, but not limited to, prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents) within 6 weeks must discontinue these medications prior to starting M3814 and avelumab on day 7, with the exception of:
• Patients with active autoimmune disease managed with systemic corticosteroids less than the equivalent of prednisone 10 mg daily
• Patients who have received acute, low dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea)
• The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension and adrenocortical insufficiency
• Patients who have undergone prior solid organ or bone marrow transplant with the exception of patients with prior renal transplant for whom dialysis may be employed in the event of graft rejection
• Patients with uncontrolled intercurrent illness (e.g., including but not limited to uncontrolled hypertension [HTN] [systolic blood pressure (BP) > 150, diastolic BP > 100], symptomatic congestive heart failure [CHF], unstable angina pectoris, ischemic myocardial infarction [MI] within 6 months, cardiac arrhythmia, recent transient ischemic attack [TIA or cerebrovascular accident (CVA)]) within 6 months
• Patients with serious active infection (e.g. requiring hospitalization and/or intravenous [IV] antibiotics) within 4 weeks prior to starting M3814 and avelumab, or signs/symptoms of infection or receiving oral or IV antibiotics for the treatment of active systemic infection within 2 weeks prior to starting M3814 and avelumab. Patients receiving prophylactic antibiotics are eligible
• Patients with known chronic hepatitis B virus (HBV) infection must have an undetectable viral load on suppressive therapy if indicated. Patients with known chronic hepatitis C (HCV) infection must have been treated and cured. Patients who are currently on curative treatment are eligible if they have an undetectable HCV viral load
• Patients with known human immunodeficiency virus (HIV) are allowed on study provided they have:
• A stable regimen of highly active anti-retroviral therapy (HAART)
• No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infection
• A CD4 count above 250 cells/mcL
• An undetectable HIV viral load on standard polymerase chain reaction (PCR)-based testing
• Patients with history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (e.g., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computed tomography (CT) scan
• Patients with known concurrent malignancy that is expected to require active treatment within two years, or may interfere with the interpretation of the efficacy and safety outcomes of this study in the opinion of the treating investigator. Superficial bladder cancer, nonmelanoma skin cancers, and low-grade prostate cancer not requiring cytotoxic therapy should not exclude participation in this trial. Patients with chronic lymphocytic leukemia (CLL) may be enrolled if they do not require active chemotherapy and their hematologic, renal and hepatic function meets criteria previously mentioned
• Patients with psychiatric illness/social situations that would limit compliance with study requirements
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to M3814 or avelumab
• Patients unable to discontinue medications or substances that are potent inhibitors, inducers or sensitive substrates of CYP3A4/5 or CYP2C19 prior to starting M3814 and avelumab are ineligible. Medications or substances that are strong inhibitors of CYP3A4/5 or CYP2C19 must be discontinued at least 1 week prior to first M3814 dose. Strong inducers of CYP3A4/5 or CYP2C19 must be stopped at least 3 weeks prior to the first dose. Drugs mainly metabolized by CYP3A with a narrow therapeutic index as judged by the investigator must stop at least 1 day prior to first M3814 dose. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product. The primary elimination mechanism of avelumab is proteolytic degradation, thus there are no contraindicated medications with respect to avelumab
• Patients who cannot discontinue concomitant proton-pump inhibitors (PPIs) prior to starting M3814 and avelumab. These must be discontinued >= 5 days prior to starting M3814 and avelumab. Patients do not need to discontinue calcium carbonate. H2 blockers are allowed provided they are taken at least 2 hours after M3814 dose
• Patients receiving sorivudine or any chemically related analogues (such as brivudine) and not able to discontinue prior to starting M3814 and avelumab are excluded
• Pregnant and lactating women are excluded from this study because M3814 and avelumab are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with M3814 and avelumab, breastfeeding should be discontinued if the mother is treated with M3814 and avelumab
• Patients who have received live vaccination within 30 days before starting M3814 and avelumab

• Ability to understand and the willingness to sign a written informed consent document
• Histologically confirmed early stage (stage T1-T2) invasive carcinoma of the breast or DCIS
• Breast conserving surgery with negative margins and negative nodes (surgical axillary staging not mandatory), stage N0 or Nx
• Treatment plan should include breast conserving surgery and adjuvant whole breast irradiation (WBI) therapy delivered with 3D-CRT or IMRT techniques
• Treatment plan includes breast tumor bed boost
• Willingness to comply with all study procedures and be available for the duration of the study
• Mastectomy of ipsilateral breast
• Lack of histologic diagnosis
• Histologic involvement of the axillary or regional nodes or metastatic disease
• Accelerated partial breast irradiation treatment plan
• Previous history of non-breast malignancy diagnosed in the past 5 years except for basal or squamous cell cancer of the skin
• Previous history of chest radiation therapy
• Previous history of ipsilateral breast cancer
• Concurrent cytotoxic chemotherapy
• Active connective tissue disease including scleroderma
• Inability or unwillingness to return for required follow up visit

• Patient must be >= 18 years of age
• Patient must have histologically confirmed IDH-WT gliomas (grade 2-4) as per World Health Organization (WHO) 2016 or 2021 classification
• Tumor tissue should be positive for FGFR-TACC gene fusion as per any local next generation sequencing (NGS) (Clinical Laboratory Improvement Act [CLIA]-approved) assay described in background section
• The disease should be recurrent or progressive glioma after initial anti-tumor treatment with at least 1 line of treatment including surgical resection, radiation therapy and/or chemotherapy.
• For patients with WHO grade 3 or 4 glioma and progressive disease < 12 weeks after completion of chemoradiotherapy, progression can be defined by the following set of criteria:
• New enhancement outside of the radiation field (beyond the high-dose region or 80% isodose line)
• If there is unequivocal evidence of viable tumor on histopathologic sampling (e.g., solid tumor areas. i.e., > 70% tumor cell nuclei in areas), high or progressive increase in Ki-67 proliferation index compared with prior biopsy, or evidence for histologic progression or increased anaplasia in tumor).
• For patients with WHO grade 3 or 4 glioma and progressive disease >= 12 weeks after completion of chemoradiotherapy, progression can be defined by the following set of criteria:
• New contrast-enhancing lesion outside of radiation field on decreasing, stable, or increasing doses of corticosteroids
• Increase by >= 25% in the sum of the products of perpendicular diameters between the first post-radiotherapy scan, or a subsequent scan with smaller tumor size, and the scan at 12 weeks or later on stable or increasing doses of corticosteroids
• For patients receiving antiangiogenic therapy, significant increase in T2/FLAIR non-enhancing lesion may also be considered progressive disease. The increased T2/FLAIR must have occurred with the patient on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy and not be a result of comorbid events (e.g., effects of radiation therapy, demyelination, ischemic injury, infection, seizures, postoperative changes, or other treatment effects).
• For patients with WHO grade 2 glioma progression is defined by any one of the following:
• Development of new lesions or increase of enhancement (radiological evidence of malignant transformation)
• A 25% increase of the T2 or FLAIR non-enhancing lesion on stable or increasing doses of corticosteroids compared with baseline scan or best response after initiation of therapy, not attributable to radiation effect or to comorbid events
• There must be measurable disease (enhancing or non-enhancing as per Response Assessment in Neuro-Oncology [RANO] or RANO-low-grade glioma [LGG] criteria), as evaluated on pre-treatment MRI
• Patient understands the procedures and investigational nature of the study drug and agrees to comply with study requirements by providing written informed consent
• Patient must have Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (or Karnofsky >= 60%)
• Absolute neutrophil count >= 1000/uL
• Hemoglobin > 8 g/dL (Patients are allowed to be transfused to this level)
• Platelets >= 100 x 10^9/L
• Serum total bilirubin =< 1.5 x upper limit of normal (ULN), unless considered due to Gilbert's disease or disease involvement following approval by the medical monitor
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 3 x institutional ULN
• Creatinine clearance > 30 mL/min (patients with mild or moderate renal impairment) based on the Cockroft-Gault glomerular filtration rate (GFR) estimation
• Patient must have normal serum phosphate level as per local laboratory parameters. (Medical management allowed)
• Patient must be recovered from any clinically relevant toxic effects of any prior surgery, radiotherapy, or chemotherapy treatment with temozolomide
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients should be New York Heart Association Functional Classification class 2B or better
• The effects of erdafitinib on the developing human fetus are unknown. For this reason and because FGFR inhibitors are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and one month after completion of erdafitinib administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and one month after completion of erdafitinib administration
• Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants
• Patients who are receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to erdafitinib
• Patients requiring any medications or substances that are moderate CYP2C9 inducers and strong CYP3A4 inducers are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
• Patients with uncontrolled intercurrent illness
• Pregnant women are excluded from this study because erdafitinib is an FGFR inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with erdafitinib, breastfeeding should be discontinued if the mother is treated with erdafitinib
• Current central serous retinopathy (CSR) or retinal pigment epithelial detachment of any grade
• Corrected QT interval (QTc) prolongation as confirmed by electrocardiography (ECG) at screening (Fridericia; QTc > 480 milliseconds)
• Patients who have previously received FGFR inhibitors

• Locally advanced or metastatic and/or unresectable HCC with diagnosis confirmed by histology/cytology or clinically by American Association for the Study of Liver Diseases (AASLD) criteria in cirrhotic participants
• Disease that is not amenable to curative surgical and/or locoregional therapies
• No prior systemic treatment for locally advanced or metastatic and/or unresectable HCC
• Measurable disease according to RECIST v1.1
• ECOG Performance Status of 0 or 1 within 7 days prior to randomization
• Child-Pugh Class A within 7 days prior to randomization
• Adequate hematologic and end-organ function
• Female participants of childbearing potential must be willing to avoid pregnancy within 5 months after the final dose of atezolizumab, within 6 months after the final dose of bevacizumab, and within 90 days after the final dose of tiragolumab/placebo
• Male participants with a female partner of childbearing potential or pregnant female partner must remain abstinent or use a condom during the treatment period and for 6 months after the final dose of bevacizumab and for 90 days after the final dose of tiragolumab/placebo to avoid exposing the embryo.
• Pregnancy or breastfeeding within 5 months after the final dose of atezolizumab, within 6 months after the final dose of bevacizumab, and within 90 days after the final dose of tiragolumab/placebo
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies
• Treatment with investigational therapy within 28 days prior to initiation of study treatment
• Treatment with locoregional therapy to liver within 28 days prior to initiation of study treatment, or non-recovery from side effects of any such procedure
• Treatment with systemic immunostimulatory agents
• Treatment with systemic immunosuppressive medication
• Untreated or incompletely treated esophageal and/or gastric varices with bleeding or that are at high risk for bleeding
• A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment
• Active or history of autoimmune disease or immune deficiency
• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan
• History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death
• Mixed histology or other subtypes/variants of HCC, including, but not limited to, known liver adenocarcinoma, fibrolamellar HCC, sarcomatoid HCC, other rare HCC variant, or mixed cholangiocarcinoma and HCC
• Co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV)
• Acute Epstein-Barr virus (EBV) infection or known or suspected chronic active EBV infection
• Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases.

The main inclusion criteria include but are not limited to the following:
• Confirmed diagnosis of CLL/SLL and active disease clearly documented to have a need to initiate therapy.
• Has at least 1 marker of disease burden.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 within 7 days before randomization.
• Has the ability to swallow and retain oral medication.
• Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have undetectable HBV deoxyribonucleic acid (DNA) viral load before randomization.
• Participants with history of hepatitis C virus (HCV) infection are eligible if HCV ribonucleic acid (RNA) viral load is undetectable at screening.
• Participants with human immunodeficiency virus (HIV) who meet ALL eligibility criteria. The main exclusion criteria include but are not limited to the following:
• Has an active hepatitis B virus/ hepatitis C virus (HBV/HCV) infection.
• Has gastrointestinal (GI) dysfunction that may affect drug absorption.
• Has diagnosis of Richter Transformation or active central nervous system (CNS) involvement by CLL/SLL.
• Has had acquired immune deficiency syndrome (AIDS)-defining opportunistic infection in the past 12 months before screening.
• Has clinically significant cardiovascular disease.
• Has hypersensitivity to nemtabrutinib or contraindication to ibrutinib or acalabrutinib, or any of the excipients.
• Has history of severe bleeding disorder.
• Has history of second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years.
• Has received any systemic anticancer therapy for CLL/SLL.
• Is currently being treated with p-glycoprotein (P-gp) substrates with a narrow therapeutic index, cytochrome P450 3A (CYP3A) strong or moderate inducers or CYP3A strong inhibitors.
• Received prior radiotherapy within 2 weeks of start of study intervention, or radiation-related toxicities, requiring corticosteroids.
• Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention. Administration of killed vaccines are allowed.
• Has received an investigational agent or has used an investigational device within 4 weeks before study intervention administration.
• Has diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication.
• Has active autoimmune disease that has required systemic treatment in the past 2 years. Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid) is allowed.
• Has active infection requiring systemic therapy.
• Participants who have not adequately recovered from major surgery or have ongoing surgical complications.